Outcomes With Drug-Coated Balloons for Treating the Side Branch of Coronary Bifurcation Lesions

Abstract: Background. Treating coronary bifurcations remains limited by technical difficulties and suboptimal long-term outcomes, often affecting the side branch (SB). Drug-coated balloon (DCB) in SB treatment could reduce neointimal hyperplasia and the risk for restenosis. Methods. We performed a systematic review of all studies published between January 2000 and February 2018 reporting the outcomes of DCB vs non-coated balloon angioplasty (BA) in the treatment of the SB in coronary bifurcation lesions. Outcomes included SB late lumen loss, SB binary restenosis, target-lesion revascularization (TLR), and major adverse cardiac event (MACE) rate. Results. Four studies with 349 patients were included in the meta-analysis (three randomized controlled trials [RCTs] and one observational study). SB stenting was performed in 7.5% vs 8.6% in the DCB and BA groups, respectively. Angiographic follow-up performed after a mean follow-up of 9.1 ± 2.1 months demonstrated that DCB was associated with lower SB late lumen loss compared with BA (mean difference, -0.19 mm; 95% confidence interval [CI], -0.37 to -0.01; P=.04). There was no difference in the risk of SB binary restenosis (odds ratio [OR], 0.52; 95% CI, 0.18-1.47; P=.22). During a mean follow-up of 15.1 ± 5.8 months, DCB and BA had similar risk of MACE (OR, 0.76; 95% CI, 0.4-1.4; P=.40), and TLR (OR, 0.85; 95% CI, 0.3-2.4; P=.76). Conclusion. Assessment of DCB for SB treatment of coronary bifurcations is limited by low power due to the small number of patients studied. Use of DCB was associated with lower SB late lumen loss, but this did not translate into improved clinical outcomes.

J INVASIVE CARDIOL 2018;30(11):393-399. Epub 2018 September 15.

Key words: coronary bifurcation lesions, drug-coated balloons, drug-eluting balloons

Bifurcation lesions account for 15%-20% of coronary lesions treated with percutaneous coronary intervention (PCI).¹ Despite the use of drug-eluting stent (DES) implantation, treating bifurcations remains limited by technical difficulties and suboptimal long-term results. Currently, the preferred approach is stenting of the main branch (MB) with a DES with provisional stenting of the side branch (SB).² However, the outcomes of PCI of bifurcated lesions remain unpredictable, mainly due to suboptimal SB outcomes.^3,4 

Drug-coated balloons (DCBs) provide mechanical expansion and release an antiproliferative drug, aiming to reduce neointimal tissue growth.⁵ The half-life of the drug in the tissues is approximately 2 months depending on the balloon type, the excipient used, and the drug concentration.^6,7 The use of DCBs has been associated with positive vessel remodeling, vascular healing inducing late lumen enlargement, and plaque reduction and stabilization.^8,9 DCBs have been shown to be an effective treatment for in-stent restenosis (ISR)^10,11 and peripheral vascular disease.^12,13 More recently, DCBs were studied in de novo coronary lesions,^8,14 especially in the treatment of small-vessel disease.^15-18

The use of DCB in the SB of bifurcation lesions could theoretically reduce neointimal hyperplasia, decreasing the risk of SB restenosis. Published studies comparing DCB with plain old balloon angioplasty (BA) in bifurcation lesions were small and consequently had low power.^19-22 We performed a systematic review and meta-analysis to examine the outcomes of DCB vs BA for treating the SB of coronary bifurcation lesions. 

Methods

Literature search. The present meta-analysis was conducted and reported according to the proposal for conducting and reporting meta-analyses of observational studies (Moose)²³ and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.²⁴ The current study is registered with the International Prospective Register for Systematic Reviews (PROSPERO: CRD42018092134). A systematic computerized search was performed through the Cochrane, EMBASE, and Medline databases from January 2000 through February 2018 using the following search terms separately and in combination: “drug-eluting balloon,” “DEB,” “drug-coated balloon,” “DCB,” “paclitaxel-coated balloon,” “PCB,” “bifurcation lesions,” and “coronary bifurcations.” A similar search strategy was performed for abstracts of the major scientific sessions (American College of Cardiology, American Heart Association, European Society of Cardiology, etc.) and Clinicaltrials.gov up to February 2018. The bibliographies of the retrieved studies and prior reviews were screened to identify any potentially relevant studies that were not retrieved through the initial search. Our search was limited to the English language. 

Study selection. We included randomized controlled trials (RCTs) and observational studies that compared outcomes of DCB vs BA for treatment of the SB of coronary bifurcation lesions. Stenting was allowed in all studies in the case of suboptimal results, defined as persistent residual stenosis, vessel recoil, or flow-limiting dissection. Treatment of the MB could be with BA, DCB, bare-metal stent (BMS), or DES in either of the treatment groups. We excluded studies that included patients with acute myocardial infarction (MI).

Data extraction and quality assessment. Two independent investigators (MD, MM) extracted the data from included studies. Variates retrieved included study characteristics, patients’ baseline characteristics, and outcomes of interest. Discrepancies among investigators were settled by consensus among the authors. The risk of bias of included studies was assessed using the New-Castle Ottawa Scale for observational studies²⁵ and the Cochrane risk assessment tool for RCTs.²⁶ 

Study outcomes. Angiographic outcomes included SB late lumen loss and SB restenosis, defined as diameter stenosis ≥50% by quantitative coronary angiography (QCA) within a previously treated segment at a follow-up coronary angiogram. Angiographic outcomes were assessed by QCA in all studies. 

The clinical outcomes included target-lesion revascularization (TLR, defined as revascularization of the bifurcation) and the risk of major adverse cardiovascular event (MACE, defined as the composite outcome of all-cause mortality, MI, and TLR). 

Outcomes were reported at the longest follow-up time available. The total number of patients was used in the analysis of clinical outcomes, while the total number of lesions was used when angiographic outcomes were assessed. Outcomes were assessed using an intention-to-treat analysis. A limited sensitivity analysis was performed for clinical outcomes when only analyzing RCTs. 

Data synthesis and statistical analysis. Statistical analysis was conducted using Review Manager software version 5.3.5 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Descriptive analyses were conducted using percentages for categorical variables and mean ± standard deviation for continuous variables. Categorical variables were compared using Fisher’s exact or Pearson’s Chi-square tests, while continuous variables were compared using two-sample t-test. Tests were two-tailed, and a P-value of ≤.05 was considered statistically significant. Summary results were reported as the mean difference for continuous outcomes with 95% confidence interval (CI) and odds ratio (OR) with 95% CI for categorical outcomes. CIs were calculated at 95% level for overall estimates effect. The choice between fixed or random-effects model was determined by evaluating the clinical, methodological, and statistical heterogeneity between the included studies as recommended by a scientific statement of the American Heart Association.²⁷ Statistical heterogeneity across trials was assessed by I² statistics, with I² statistic values <25%, 25%-50%, and >50% interpreted as low, moderate, and high degree of statistical heterogeneity, respectively.²⁸ For OR calculations, we used a fixed-effects model (the Mantel-Haenszel method) in the absence of a high degree of heterogeneity or the DerSimonian and Laird random-effects model when a high degree of heterogeneity was suspected. For mean difference calculation, a fixed or random-effects generic variance method was used in the presence or absence of significant heterogeneity, respectively. Weighted mean follow-up durations were calculated with the sample size being the weight. Potential publication bias was assessed using Egger’s test by visual examination of a funnel plot.²⁹

Results

Characteristics of the included studies and quality assessment. The study selection process is illustrated in Figure 1. Four studies^19-22 (one observational study and three RCTs) with a total of 349 patients met our inclusion criteria. The characteristics of the included studies are described in Table 1.

The DCB arm included 174 patients, while the BA arm included 175 patients. Clinical follow-up was available in 100% of patients, while angiographic follow-up was completed for 81.7% of lesions. The weighted mean follow-up duration was 15.1 ± 5.8 months for clinical outcomes and 9.1 ± 2.1 months for angiographic outcomes.

All studies met the inclusion criteria with no evidence of publication bias (Supplemental Figure S1). Bias assessment as per the New-Castle Ottawa Scale for observational studies and the Cochrane assessment tool for RCTs is illustrated in Supplemental Tables S1 and S2. 

Baseline characteristics of the included cohorts. The baseline characteristics of the included patients and lesions are summarized in Tables 2 and 3. Our pooled cohort population included mostly men (72.5%). The prevalence of diabetes mellitus (DM) was 28%. SB stenting was performed in a similar proportion of the two study groups (7.5% in the DCB group vs 8.6% in the BA group; P=.70). The percentage of Medina type 0,0,1 lesions³⁰ was 70.7% in the DCB group vs 66.3% in the BA group (P=.37). The SB reference diameter was larger in the DCB group (2.5 ± 0.4 mm) vs the BA group (2.4 ± 0.3 mm; P<.01).

Angiographic outcomes. The clinical and angiographic outcomes are summarized in Figure 2. In a total of 280 lesions, DCB was associated with less late lumen loss than BA (mean difference, -0.19 mm; 95% CI, -0.37 to -0.01; P=.04; I²=50%) during a mean follow-up of 9.1 ± 2.1 months. There was no difference in risk of SB restenosis (OR, 0.52; 95% CI, 0.18-1.47; P=.22; I²=49%) between the two groups (Figure 3). There was no difference in the rate of MB restenosis between the two groups (OR, 1.08; 95% CI, 0.29-4; P=.91; I²=61%).

Target-lesion revascularization. During a mean follow-up of 15.1 ± 5.8 months, there was no difference in the risk of TLR between DCB and BA (OR, 0.85; 95% CI, 0.3-2.4; P=.76; I²=54%). In a sensitivity analysis including only RCTs, DCB and BA still had a similar risk of TLR (OR, 1.1; 95% CI, 0.24-4.93; P=.91; I²=62%) (Figure 4).

Major adverse cardiac events. The use of DCB was associated with a similar risk of MACE (OR, 0.76; 95% CI, 0.4-1.4; P=.40; I²=26%) compared with BA. In a limited analysis including only RCTs, DCB remained associated with similar risk of MACE as BA (OR, 0.92; 95% CI, 0.39-2.16; P=.85; I²=29%) (Figure 5).

Discussion

Our systematic review and meta-analysis revealed that there are few published data on the use of DCB of treating the SB in bifurcation lesions, limiting the power to detect differences in angiographic and clinical outcomes. In studies that mainly included bifurcation lesions with only SB involvement, the use of DCB was associated with less SB late lumen loss as compared with BA, but both groups had similar incidence of TLR, MACE, and SB binary restenosis.

Coronary bifurcation PCI is complex, with increased complication rates compared with PCI of non-bifurcated lesions.³¹ The most common approach to bifurcation PCI currently is stenting of the MB with provisional SB stenting.³² However, the optimal technique for treating SB is poorly defined. SB stenting may be associated with inadequate ostium coverage or protrusion of stent struts into the MB and has been associated with increased risk of ISR and stent thrombosis.^32-34 

The use of DCB may have some advantages over DES in bifurcation lesions. DCB provides a smaller profile compared with DES, allowing better SB access. The lack of foreign body implantation with DCB obviates the risk for stent thrombosis and may allow for a shorter duration of dual-antiplatelet therapy compared with DES.³⁵ However, the use of DCB may result in high residual stenosis and dissections, potentially necessitating bail-out stenting.³⁶ Yet, preliminary results show that DCB-induced dissections may heal within a few months without always requiring stenting.³⁷ 

Single-arm trials have studied the use of DCB to SB in coronary bifurcations.^38-43 In the PEPCAD V (Paclitaxel Eluting PTCA Balloon in Coronary Artery Disease) treatment of bifurcation lesions with a drug-eluting balloon trial, DCB to MB and SB followed by BMS to MB resulted in 7.7% SB restenosis over 9 months.³⁹ Schulz et al used DCB in both MB and SB with 7.7% TLR and MACE at 4 months.³⁸ In a recently published, single-arm, prospective study including patients with Medina 0,0,1 lesions and associated MI, the Dior DCB (Eurocor GmbH) was associated with MACE rate of 14.3% at a mean follow-up time of 12 months. In earlier feasibility studies, a first-generation matrix-free DCB was used, which has been shown inferior to DCBs, with a matrix consisting of an excipient in addition to the drug, facilitating rapid absorption of paclitaxel into the vascular wall.⁴⁴ 

In our study, DCB to the side branch was associated with less SB late lumen loss compared with BA only. The rate of binary restenosis of SB was numerically lower in the DCB group (10.6% vs 18.8%; P=.22) over 9 months. However, our results did not account for the baseline size of the SB or the severity and hemodynamic significance of SB lesions. In our cohort, the SB reference diameter was larger in the DCB group (2.5 ± 0.4 mm) compared with the BA group (2.4 ± 0.3 mm; P<.01). 

DCB had a similar risk for adverse clinical outcomes with BA in our study, even when only RCTs were included in the analysis. However, even with pooling the data from all available studies, our study remains underpowered to detect differences in clinical outcomes. 

Study limitations. First, due to the small number of studies, patients, and events, the study had low power for detecting differences in clinical events. Second, TLR was defined as revascularization of the bifurcation, which includes revascularization of proximal or distal MB, which might dilute a potential beneficial effect of DCB on the SB. Third, all studies included only paclitaxel-coated balloons and older-generation DES options. Fourth, subgroup analysis based on SB size and the severity and hemodynamic significance of SB lesions could not be performed. Fifth, most lesions (68.5%) included in the analyzed studies were Medina class 0,0,1; hence, our findings may not apply to all bifurcation lesions. Finally, we encountered a high degree of heterogeneity in our primary analysis, which can be explained by the differences in study methodology and protocols, patient characteristics, and operator expertise. 

Supplemental Figure/Tables

Conclusion

Assessment of DCB for SB treatment of coronary bifurcations is limited by low power due to the small number of patients studied. Use of DCB was associated with lower SB late lumen loss, but this did not translate into improved clinical outcomes. Further study is needed for assessing the role of DCBs in SB lesion treatment.

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From the ¹Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, Minnesota; ²Division of Cardiovascular Medicine, Department of Medicine Hennepin Healthcare, Minneapolis, Minnesota; ³Division of Cardiology, Cook County Hospital, Chicago, Illinois; ⁴Division of Cardiology, Department of Medicine, University of Arkansas, Little Rock, Arkansas; ⁵Division of Cardiology, Ain Shams University, Cairo, Egypt; and ⁶Division of Cardiology, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Shishehbor reports education and consulting without compensation for Abbott Vascular, BioClinica, Boston Scientific, Medtronic, Covidien, Philips/Spectranetics, Cook, Terumo, RAM Medical Innovations, LamaMed, Volcano and Shockwave Medical. Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, Amgen, CSI, Elsevier, GE Healthcare, and Medtronic; grant support from Boston Scientific, Osprey, Regeneron, and Siemens; other income from the American Heart Association (Associate Editor, Circulation), Cardiovascular Innovations Foundation (Board of Directors), and the Society of Cardiovascular Angiography and Interventions (Board of Trustees); shareholder in MHI Ventures. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted June 17, 2018 and accepted July 3, 2018.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Minneapolis Heart Institute, 920 E. 28th Street #300, Minneapolis, MN 55407. Email: esbrilakis@gmail.com